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Study in Twins Suggests Solvents May Raise Parkinson Disease Risk

Samson, Kurt

doi: 10.1097/01.NT.0000410070.44352.53
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Investigators reported that twins who had been exposed to trichloroethylene had a higher incidence of Parkinson disease in their mid-60s when compared to their siblings who had not been exposed.

Exposure to a compound commonly used in industrial solvents and household cleaning products may significantly increase the risk of Parkinson disease (PD) later in life, according to a new epidemiological study comparing lifetime exposure among sets of twins.

The findings, published in an early online release Nov.14 in the Annals of Neurology, found that twins who had been exposed to trichloroethylene (TCE) had a higher incidence of PD in their mid-60s when compared to their siblings who had not been exposed. Rates were also elevated in twins exposed to perchloroethylene (PERC) and carbon tetrachloride (CCI), but the association failed to reach statistical significance.

“What we discovered was a six-fold increase with TCE exposure, and almost the same for PERC,” Samuel M. Goldman, MD, MPH, associate professor at the Parkinson's Institute and Clinical Center in Sunnyvale, CA, told Neurology Today in a telephone interview. “To the best of our knowledge, this is the first confirmation of a significant association between TCE exposure and PD risk in a population-based study.”

Caroline M. Tanner, MD, PhD, the institute's clinical research director and a prominent researcher in the field, also co-authored the study, which was funded by the NINDS.

Although earlier case reports have hinted that environmental association to solvents might increase PD risk, the new study is the first to use an analytical epidemiologic design, as well as the first to compare the link in twins who had never worked with solvents and their siblings who had.

The study involved 99 pairs of twins, where one but not the other had PD, and focused primarily on occupational exposure. The subjects were drawn from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort. Each twin answered detailed questions about lifetime occupations and hobbies, including task-specific questionnaires that focused on possible solvent exposure. Researchers reviewed the responses without being aware of any respondent's PD status.

In addition to TCE, PERC, and CCI, the team also evaluated potential exposures to toluene, xylene, and n-hexane, all of which have been suspected in case reports of PD. They analyzed probability of exposure given the type of task performed by an individual, the length of time they might have worked with a solvent, and the decade when they were performing such tasks.

TCE was initially used as a general anesthetic and for decaffeinating coffee, but the US FDA banned such use in 1977. However the agent continues to be used as a dry-cleaning and mechanical degreasing agent. It also is used as an additive in many common household products, including soaps, adhesives, sealants, paints, carpet cleaners, spot removers and polishes.

Although the study focused on workplace exposure, the authors noted that exposure to TCE and other solvents in the environment makes the findings significant from a public safety perspective as well.

“One remarkable observation made in all of the reports linking TCE exposure with PD is that it can take 10 to 40 years between exposure and clinical symptoms,” Dr. Goldman said. “This suggests that exposure may trigger a degenerative cascade dependent on the passage of time, which would provide a critical window of opportunity to arrest the disease process before symptoms are manifested.”

The findings were consistent with known pathological and neurochemical features of PD in rodent models of TCE-induced parkinsonism, he noted, including selective dose-dependent loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), as well as selective accumulation of alpha-synuclein protein in the dorsal motor nucleus of the vagus nerve. Moreover, these are both consistent with pathological findings in PD patients.

“If you look at the data in rodent models it is really impressive, especially for changes in dopaminergic neurons, microglia, alpha-synuclein, and mitochondrial activity. I think that this is definitely a red flag, and the data from animal models is compelling,” Dr. Goldman noted.

Most of the respondents with PD in the study were 65 years of age or older, but PD can have a decades-long latency period and exposure could have occurred years before they developed disease symptoms, he explained.

“These products are still out there,” Dr. Goldman noted, not only in cleaning products but also in groundwater. “There is plenty of epidemiological data on cancer and solvent exposure, but there is surprisingly little on solvents and neurological disease,” he said.

In a study involving 110 PD patients published last February, Drs. Tanner, Goldman and colleagues reported that exposure to two agricultural pesticides, rotenone and paraquat, was associated with 2.5 times higher risk of developing PD.

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This is a comprehensive and well designed study, although it was limited by the size of the sample population and possible recall bias by subjects asked to remember specifics about their work history going back decades, according to Alberto Ascherio, MD, professor of epidemiology and nutrition at Harvard School of Public Health in Boston.

“While the findings are interesting and very provocative, they require further confirmation before we can conclude with confidence that exposure to TCE causes Parkinson disease,” he told Neurology Today in a telephone interview.

He said the major weakness in the report, which the authors acknowledged, is reliance on proxy interviews to assess exposures.

“A better understanding of any association will have to come from specific data on the dose and amount of exposure each individual has experienced, something that is very difficult to determine retrospectively,” he said. “Data from large occupational cohorts may contribute to understand the role of TCE and other solvent as risk factors for Parkinson disease.”

Janis Miyasaki, MD, associate professor of neurology at the University of Toronto, and associate clinical director of the Movement Disorders Center at Toronto Western Hospital, complimented the researchers on their work, but also agreed that many questions remain unanswered.

“This group of researchers has an excellent record of doing meticulous studies, and Dr. Tanner is one of the leaders in this field. However, research is increasingly suggesting that PD is not a single entity but a spectrum of different movement disorders,” she told Neurology Today in a telephone interview.

“If you look at patients with a diagnosis of PD, the best clinical information indicates that as many as 20 percent of them do not have the disease, and maybe more. What they have is parkinsonism of some type, and we are just beginning to recognize this.”

She advised individuals not only to reduce exposures to such compounds, but also to adopt healthier lifestyles to avert potential neurological problems later in life, especially given the unknown risk of exposure to such solvent contaminants in the environment.

“Surveys like this are the next best thing to real experiments, and we cannot experiment on humans, but we have to take them with a grain of salt. For instance, how many persons were exposed to the same chemicals but did not develop PD?” she asked.

Moreover, even identical twins are not identical when it comes to expression of different genes that may play a role in PD, she added.

“The difficulty is teasing out the risk given these research limitations.”

Findings like this, coupled with the disease's long latency period, underscore the need to develop biomarkers for PD, Dr. Miyasaki told Neurology Today.

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• Goldman SM, Tanner CM, et al. Solvent exposures and parkinson disease risk in twins. Ann Neurol 2011;E-pub 2011 Nov. 14.
• Gash DM, Rutland K, Hudson NL, et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 2008:63:184-192.
• Tanner CM, Goldman SM, Umbach DM, et al. Rotenone, paraquat and Parkinson's disease. Environ Health Perspect 2011;119:866-872.
©2011 American Academy of Neurology